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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
6-Aminoquinoline is an important quinoline derivative with broad applications in antimalarial and antimicrobial drug research. Derivatives like chloroquine and quinapyramine are used to treat malaria and certain parasitic infections. Additionally, 6-Aminoquinoline serves as a fluorescent probe and key intermediate for organic synthesis, used in DNA, RNA binding studies and the development of novel anti-infective drugs.
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Jang, Mingyeong ; Lim, Taeho ; Park, Byoung Yong ; Han, Min Su ;
Abstract: In this study, we developed a metal-free and highly chemoselective method for the reduction of aromatic nitro compounds. This reduction was performed using tetrahydroxydiboron [B2(OH)4] as the reductant and 4,4'-bipyridine as the organocatalyst and could be completed within 5 min at room temperature. Under optimal conditions, nitroarenes with sensitive functional groups, such as vinyl, ethynyl, carbonyl, and halogen, were converted into the corresponding anilines with excellent selectivity while avoiding the undesirable reduction of the sensitive functional groups.
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CAS No. : | 580-15-4 |
Formula : | C9H8N2 |
M.W : | 144.17 |
SMILES Code : | NC1=CC=C2N=CC=CC2=C1 |
MDL No. : | MFCD00006803 |
InChI Key : | RJSRSRITMWVIQT-UHFFFAOYSA-N |
Pubchem ID : | 11373 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319 |
Precautionary Statements: | P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With palladium 10% on activated carbon; hydrogen; In tetrahydrofuran; methanol; at 20℃; for 2h; | Synthesis of 89 To a methanol (50 ml)-tetrahydrofuran (50 ml) suspension of 88 (5.00 g, 28.71 mmol), 10% Pd-C (moisture of about 50%; 1.00 g) was added under a hydrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. The catalyst was removed by filtration and the solvent of the filtrate was distilled off under reduced pressure to obtain 89 (4.14 g, 100%) as a pale yellow solid. mp 116-117C APCI-MS m/z 145[M+H]+ |
> 99% | With lithium hydroxide monohydrate; palladium diacetate; 4,4,5,5-tetramethyl-1,3,2-dioxaborolane; In dichloromethane; at 25℃; for 12h;Schlenk technique; Inert atmosphere; | Replace the gas environment in the Shrek tube with a nitrogen environment, add 6-nitroquinoline 0.25 mmol, palladium acetate 0.005 mmol, methylene chloride 0.5 mL, add pinacol borane 0.775 mmol, water 0.55 mmol, room temperature with stirring The reaction was carried out under conditions for 12 hours. The reaction solution obtained after the reaction was completed was subjected to column chromatography, and the target product obtained with a yield of> 99% was a pale yellow solid. |
95% | With hydrogen; In methanol; N,N-dimethyl-formamide; at 50℃; under 6080.41 Torr; for 22h;Inert atmosphere; Autoclave; | General procedure: The hydrogenation of nitrobenzene (Table 1, entry 2) is given as an example.Nitrobenzene (2a) (1.88 g, 15.3 mmol) was charged into an Ar-filled 100 mL glass autoclaveequipped with a Teflon-coated magnetic stirring bar. Methanol (10 mL) degassed by three freeze-thaw cycles was introduced via Teflon cannula, followed by the addition of a solution of thePd-NPs catalyst in DMF (5.0 mM, 60 μL, 0.30 μmol, S/Pd = 51,000:1). Hydrogen wasintroduced into the reaction vessel until the pressure gauge indicated 8 atm, and then the pressurewas carefully released to 1 atm by opening the stop valve. This procedure was repeated five times,and finally hydrogen was pressurized to 8 atm. The vessel was placed into a water bath controlledat 50 C, and the reaction mixture was vigorously stirred for 40 h. After careful venting of thehydrogen, the reaction mixture was concentrated under a reduced pressure.1,3,5-Trimethoxylbenzene (101.0 mg, 0.601 mmol) was added as an internal standard for the NMRanalysis, and the produced aniline (3a) was quantified (99%).The reaction mixture was concentrated to approximately half the original volume under a reducedpressure, followed by dilution with ether (15 mL). The ethereal solution was extracted by 3 Mhydrochloric acid (15 mL 3, 10 mL 2) to remove the internal standard for NMR analysis.The combined aqueous solution was basified by the addition of 3 M NaOH until the pH of thesolution became >12, and the alkaline solution was extracted by ether (15 mL 3). Thecombined extracts were washed with brine and dried over anhydrous sodium sulfate. Afterremoval of the drying agent by filtration, the solution was concentrated under a reduced pressure.The residual oil was purified by bulb-to-bulb distillation, giving pure aniline as a colorless oil (1.14g, 80%). |
93% | With palladium diacetate; hydrazine hydrate monohydrate; potassium hydroxide; In lithium hydroxide monohydrate; at 50℃; for 8h;Inert atmosphere; Green chemistry; | General procedure: To an oven-dried reaction flask with Teflon coated stir bar purgedwith argon, Pd(OAc)2 0.01 mmol, IL4 0.08 mmol, KOH (or K2CO3)0.30 mmol, nitroarene 1 1.0 mmol and degassed HPLC grade water1.5 mL were added, and the mixture was stirred for 5 min under argonat room temperature. Then, 0.5 mL of hydrazine hydrate aqueous solution(~5.0 mmol) was syringed into the flask at the same temperature.After stirring for additional 5 min, the reaction was heat to 50 C,and stirring for 8 h under argon. After completion, the reaction mixturewas extracted by methyl tertiary butyl ether (MTBE) (3 × 2 mL), andthe organic layer was collected and filtered through a bed of silica gellayered over Celite. The volatiles were removed in vacuo to afford theproduct 2. In some cases, further column chromatography on silica gelwas required to afford the pure desired products. |
91% | With hydrogen; In methanol; at 20℃; | The solution of 6-nitroquinoline (174.2 mg, 1 mmol) in methanol (10 mL) wastreated with Pd/C (10%, 14.0 mg). the reaction mixture wasvigorously stirred under an atmosphere of hydrogen at roomtemperature. +e progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixturewas then filtered and concentrated in vacuo to give the crudeproduct. The crude product was purified by column (ethylacetate : petroleum ether: 4) to afford the product 2(131.1 mg, 91.0%) as white solid. m.p. 116.8-119.0C. 1HNMR (600 MHz, CDCl3) 2: 8.64 (d, J 4.0 Hz, 1H), 7.89 (t,J 9.7 Hz, 2H), 7.25 (t, J 4.8 Hz, 1H), 7.14 (dd, J 9.0 Hz,2.6 Hz, 1H), 6.88 (d, J 2.5 Hz, 1H), 3.84 (brs, 2H). |
90% | With tetrahydroxydiborane; copper (II) acetate; In acetonitrile; at 100℃; for 24h;Inert atmosphere; | 6-nitroquinoline (0.6mmol, 114.1mg), Cu(OAc)2 (0.03mmol, 6.0mg) and tetrahydroxydiboron (0.9mmol, 80.7mg), acetonitrile (1mL), under nitrogen protection, 100 C After reacting for 24 hours, the reaction was monitored by TLC, 10 mL of water was added, ethyl acetate (10 mL×3) was added, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (V petroleum ether: V ethyl acetate = 3:1) to obtain 77.9 mg of white solid, which is to obtain the target compound with a yield of 90%. |
87% | With hydrazine hydrate monohydrate; In ethanol; at 80℃; for 1h;Inert atmosphere; | General procedure: Hydrazine hydrate was chosen as the hydrogen donor for the low emission of pollutants. In a typical procedure, hydrazine hydrate (4 equiv) was added into the reactor which containing fresh prepared catalyst as described above. Then the reactor was put into a preheated oil bath with a stirring speed of 500 rpm, and the substrate (1 mmol)dissolved in 1 mL ethanol was added drop-wisely under argon. The reactions were monitored by TLC. After the reaction, the reaction mixture was vacuum filtered through a pad of silica on a glass-fritted funnel and an additional 15 mL of ethyl acetate (5 mL portions) was used to rinse the product from the silica, the filtrate was concentrated in vacuum and analyzed by GC. Products were purified by column chromatography and identified by 1H NMR and 13C NMR. |
83% | With tetrahydroxydiborane; 5%-palladium/activated carbon; lithium hydroxide monohydrate; In acetonitrile; at 50℃; for 24h; | General procedure: Nitrobenzene (0.6mmol), 5wt% Pd/C (0.5mmol %, 0.003mmol), H2O (10 equiv, 6.0mmol), B2(OH)4 (3.3 equiv, 2.0mmol), and CH3CN (1.0mL) were added in a 10mL tube. The reaction mixture was stirred at 50C for 24h. When the reaction was complete monitored by TLC, the mixture was cooled to room temperature. Water (5mL) was added, and extracted with EtOAc (3×5mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give aniline 2a (55mg, 99%). |
83% | General procedure: The nitro compound (1 equiv), HFIP (10 equiv), Fe powder (5 equiv) were mixed in a tube. Then 2 N HCl aqueous solutions was added to the reaction mixture. After stirring at room temperature for 30 min, the reaction mixture was neutralized with sat. NaHCO3 (aq.) and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was then purified by column chromatography on silica gel to furnish the desired amine product. | |
75% | With tetrahydroxydiborane; copper (II) acetate; In acetonitrile; at 80℃; for 24h;Schlenk technique; | General procedure: A 20 mL Schlenk tube was charged with 8-nitroquinoline (1k; 87 mg, 0.5 mmol), Cu(OAc)2 (4.5 mg, 0.025 mmol), B2(OH)4(135 mg, 1.5 mmol), and MeCN (2.0 mL). The mixture was stirred at 80 C for 24 h, then cooled to room temperature and concentrated under reduced pressure. Similar workup to 2a gave a brown solid (4a: 63 mg, 87% yield). |
65% | With tetrahydroxydiborane; lithium hydroxide monohydrate; at 80℃; for 8h; | General procedure: Nitro aromatic (1.0 mmol), B2(OH)4 (5.0 equiv, 5.0 mmol), and H2O (3.0 mL) were added in a10 mL tube. The reaction mixture was stirred at 80 C for 8 h. When the reaction was completemonitored by TLC, the mixture was cooled to room temperature, extracted with ethyl acetate (3 ×20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, andconcentrated under reduced pressure. The residue was purified by silica gel columnchromatography. |
46% | With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; for 24h; | INTERMEDIATE 1 Synthesis of 6-Amino-quinoline A suspension of 6-nitro-quinoline (8.7 g, 5 mmol), palladium on charcoal (10 %) (0.1 g) in methanol (0.2 L) was hydrogenated at room temperature for 24 with stirring. The catalyst was filtered and the solvent evaporated to yield a yellow solid. Crystallisation from ethyl acetate yielded the pure title compound as a pale yellow solid (3.3 g, 46 %). MS m/z: 145 [[M+H+]. IH] NMR (270 MHz, [CHC13-D)] [8] ppm 3.89 (s, 2 H) 6.87 (d, [J=2.] 64 Hz, 1 H) 7.14 [(DD,] [J=8.] 97,2. 64 Hz, 1 H) 7.25 [(DD,] [J=8.] 44,4. 22 Hz, [1] H) 7. [88 (DD, J=7.] 92,1. [58] Hz, 1 H) 7.90 (d, [J=8.] 97 Hz, 1 H) 8.63 [(DD,] [J=4.] 22,1. [58] Hz, 1 H). |
98%Chromat. | With hydrazine hydrate monohydrate; In ethanol; at 70℃; for 1h;Schlenk technique; Sealed tube;Catalytic behavior; | General procedure: Pd cNPs/CFe3O4 (20mg, 0.73mol% of Pd), aromatic nitro compounds (1mmol),N2H4.H2O (3mmol), and EtOH (3mL) were taken in a schlenk tube with a teflon stopcock, sealed and heated at 70C for a given time with constant stirring. After the completion of reaction, the catalyst was separated by an external magnet and reaction mixture was decanted. The solvent was evaporated and the residue was subjected to GC analysis (retention time of nitroaromatic compounds was used as internal standard) followed by column chromatography for further purification. The purified compounds were characterized by 1H NMR spectroscopy using CDCl3 as solvent and TMS as internal standard. The spectral details and spectra are given in supporting information section (Fig. S4a-S4l). |
With hydrogen; In methanol; at 120℃; under 11251.1 Torr; for 3h; | General procedure: Typically, 0.5 mmol of nitrobenzene, 20 mg of Co-NSPC-X catalyst and 5 mL of methanol were added into a 30 mL stainless steel autoclave, and the autoclave was pressurized to 1.5 MPa. Then the reactor was placed into oil bath and heated to 120 C with vigorous stirring. After 2 h, the autoclave cooled down to room temperature and the hydrogen gas was carefully released. After the catalysts were removed by filtration, the remaining liquid mixture was analyzed on GC 9890 equipped with a DB-1701 column and a flame ionization detector (FID). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With sodium azide; tert.-butylnitrite; In water; tert-butyl alcohol; at 20℃;Sealed tube; | General procedure: t-BuOH (1.0 mL/mmol) was added to NaN3 (3 equiv) moistened with water (150 μL/mmol). The arylamine (1 equiv) and t-butyl nitrite (20 equiv) were added in sequence to the stirring solution. Stirring was continued at rt upon completion of the reaction as indicated by TLC, water (1.4 mL/mmol) was added and the mixture was extracted with EtOAc (2.3 mL/mmol 3). The combined organic layers were dried with MgSO4 and evaporated under reduced pressure. The resulting crude product was purified as specified. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.6% | With pyridine; In dichloromethane; at 5 - 20℃; for 24.9167h; | Preparation of N-quinolin-6-ylmethanesulfonamide; 150 g of <strong>[580-15-4]6-aminoquinoline</strong>, 3000 ml of dichloromethane and then 90.5 g of pyridine are introduced into a 5-liter three-necked round-bottomed flask equipped with a mechanical stirrer, a 250 ml addition funnel and a nitrogen inlet. A clear yellow solution is obtained. The medium is stirred and cooled to 5+/-2 C. 123.9 g, i.e. 1.06 eq., of methanesulfonyl chloride are added over 30 minutes at 5+/-2 C. The medium turns blood red and, at the end of the addition, the temperature of the medium is 12 C. Ten minutes after the end of the addition, and still at 5+/-2 C., the reaction medium suddenly thickens (heterogeneous pink reaction medium). 15 minutes after the end of the addition, the cooling bath is removed and the mixture is allowed to warm to room temperature. The medium thickens, and 450 ml of dichloromethane are then added. The medium becomes more stirrable. The reaction mixture is continued to be stirred for about 24 hours at room temperature. The mixture is then cooled to 14+/-2 C. and 499 ml of tap water are added over 5 minutes. 408 ml of 5N sodium hydroxide are then added over 30 minutes. The addition of sodium hydroxide is slightly exothermic, +4 C. The pH at the end of the addition of the sodium hydroxide should be 12, and if not, further sodium hydroxide is added to reach this value. The phases are separated by settling. Two clear yellow phases are obtained. The aqueous phase is washed with 3×300 ml of dichloromethane. The aqueous phase is cooled to 14+/-2 C. 6N hydrochloric acid is added over 30 minutes. From the addition of the first few ml, a thick yellow precipitation is observed. After continued addition of hydrochloric acid, a red precipitate appeared suddenly. The mixture is stirred at 10 C. for a further 30 minutes and is then left to warm to room temperature. 990 ml of 10% sodium bicarbonate in water are added over 30 minutes at room temperature. At the end of the bicarbonate addition, the pH should be between 8 and 9, and if it is not, an adjustment needs to be made by further addition of sodium bicarbonate solution. A pink colored thick foam is obtained. The mixture is stirred overnight at room temperature and is then cooled to 2+/-2 C. for one hour, followed by filtration. The filtrate is rinsed with 3×150 ml of tap water and the pink solid is placed in an oven under vacuum (100 mmbar) at 35 C. to constant weight. 182.8 g of N-quinolin-6-ylmethanesulfonamide are obtained, i.e. a yield of 80.6%. 1H NMR spectrum (300 MHz )-δ in ppm-in DMSO-d6: 3.12 (s, 3H); 7.51 (dd, J=4.5 and 8.5 Hz, 1H); 7.63 (dd, J=2.5 and 9.0 Hz, 1H); 7.75 (d, J=2.5 Hz, 1H); 9.01 (d, J=8.5 Hz, 1H); 8.32 (broad d, J=8.5 Hz, 1H); 8.82 (dd, J=2.0 and 4.5 Hz, 1H); 10.2 (broad s, 1H). |
69% | With pyridine; at 20℃; for 18h; | General Procedure: A solution of <strong>[580-15-4]6-aminoquinoline</strong> (2.50 g, 17.36 mmol) in dry pyridine (86 mL) was treated with methanesulfonyl chloride (1.48 mL, 2.19 g, 19.10 mmol) followed by stirring at RT for 18 h. The mixture was concentrated in vacuo with toluene (3 x) to remove the pyridine. The red solid was suspended in saturated sodium bicarbonate solution and stirred for 30 min. The solid was collected by filtration and washed with water. The solid was dissolved in methanol and treated with Darco G-60 and filtered through celite. Concentration of the filtrate afforded 12a (2.65 g, 69%) as a buff-colored solid. 1H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1 H), 8.81 (dd, J = 4.2, 1.7 Hz, 1 H), 8.31 (d, J = 8.4 Hz, 1 H), 8.00 (d, J = 9.0 Hz, 1 H), 7.73 (d, J = 2.4 Hz, 1 H), 7.60 (dd, J = 9.0, 2.5 Hz, 1 H), 7.50 (dd, J = 8.3, 4.2 Hz, 1 H), 3.10 (s, 3 H). Mass Spectrum: +ESI m/z (rel abundance) 223 (100, M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With C15H23N3Pol(1+)*Cl(1-); benzotriazol-1-ol; In dichloromethane; at 35℃; | Example 2a; N-(Quinolin-6-yl)-6-(sulfamoylamino)hexanamide (5a) Step 1: tert-Butyl 6-oxo-6-(quinolin-6-ylamino)hexylcarbamate (1a) To a solution of N-Boc caproic acid (0.23 g, 1.0 mmol) in DCM (5 ml) was added PS-carbodiiminde (0.8 g, 1.1 mmol). After 10 minutes <strong>[580-15-4]6-aminoquinoline</strong> (0.1 g, 0.7 mmol) and HOBt (0.13 g, 1.0 mmol) were added and stirred over night at 35 C. The mixture was filtered and concentrated. The residue was purified by silica gel column chromatography with gradient of EtOAc (20-100%) in Hexane to afford 1a (0.2 g, 56%) as a beige solid. LRMS (ESI): (calc.) 357.2; (found) 358.3 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In N,N-dimethyl-formamide; at 110℃; for 0.5h; | Example 271; (4Z)-6-Bromo-4-[(quinolin-6-ylamino)methylene]isoquinoline-1,3(2H,4H)-dione; A mixture of 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (141 mg, 0.5 mmol), <strong>[580-15-4]6-aminoquinoline</strong> (72.2 mg, 0.5 mmol) in 1 mL of N,N-dimethylformamide is heated at 110 C. for 0.5 h. After cooling in the refrigerator, the precipitate is collected, and washed with N,N-dimethylformamide (DMF) and ether to give 169 mg (85%) of yellow solid. MS (ESI) m/z 394.0, 396.0 (M+H)+1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In N,N-dimethyl-formamide; at 110℃; for 0.5h; | Example 272; (4Z)-6-Iodo-4-[(quinolin-6-ylamino)methylene]isoquinoline-1,3(2H,4H)-dione; A mixture of 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (164.5 mg, 0.5 mmol), <strong>[580-15-4]6-aminoquinoline</strong> (72.2 mg, 0.5 mmol) in 1 mL of N,N-dimethylformamide is heated at 110 C. for 0.5 h. After cooling in the refrigerator, the precipitate is collected, and washed with N,N-dimethylformamide (DMF) and ether to give 189 mg (85%) of yellow solid. MS (ESI) m/z 442.0 (M+H)+1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | To a suspension of 5-bromo-1-chloroisoquinoline (3.0 g, 12.4 mmol) in iPrOH (100 mL), <strong>[580-15-4]6-aminoquinoline</strong> (4.5 g, 31.2 mmol), 4M HCI-dioxane (5 mL) and MeOH (15 mL) were added and stirred at 80 C 3dys. After cooling, the mixture was evaporated to remove solvent then suspended into AcOEt. The mixture was basified with NaHCO3aq. then formed precipitate was collected by filtration and washed with AcOEt to give the title compound (3.4 g, 78%). | |
78% | To a suspension of5-bromo-1-chloroisoquinoline (4) (3.0 g, 12.4mmol) iniPrOH (100 mL), <strong>[580-15-4]6-aminoquinoline</strong> (4.5g, 31.2mmol), 4MHCI-dioxane (5 mL) andMeOH (15 mL) were added and stirred at80 C for 3 days. After cooling, the mixture was evaporated to remove solvent then suspended into AcOEt. The mixture was basified withNaHC03aq. then formed precipitate was collected by filtration and washed with AcOEt to give the title compound (5) (3.4 g, 78 %). MS (ESI) (M+H) + 350,352. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With benzotriazol-1-ol; diisopropyl-carbodiimide; In dichloromethane; at 20℃; | A solution of Z-Val-Pro-OH (217.4 mg, 0,62 MMOL) in dichloromethane (1,5 mL), was successively treated at room emperature. with 1- HYDROXIBENZOTRIAZOL (84,3 mg, 0,62 mmol), N, N'-diisopropylcarbodiimide (97,2 RL, 0,62 MMOL) and 6-AMINOQUINOLINE (75 mg, 0,52 MMOL). The stirring was continued until the complete disapperance of the starting material (overnight). Then, the solvent was evaporated, the residue was dissolved in ethyl acetate and washed with citric acid (10%), NaHCOs (10%) and brine. The organic layer was dried (NA2SO4) and evaporated leaving a residue that was purified by CCTLC on the chromatotron with HEXANE/ETHYL acetate (1: 4) to yield H (20 % yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With hydrogenchloride; hydroxylamine hydrochloride; sodium sulfate; In ethanol; water; for 0.25h;Heating / reflux; | d) 3-H-Pyrrolo[3,2-f]quinoline-1,2-dione; [0128] To a 1 L flask was added sodium sulfate (0.6 mol) and water (100 mL) and the mixture was stirred until the solids dissolved. To this solution was added a solution of <strong>[580-15-4]6-aminoquinoline</strong> (0.033 mol) in 1N aqueous hydrochloric acid (50 mL) and ethanol (10 mL). The mixture was stirred and chloral (0.036 mol) was added. To the resulting solution was added a solution of hydroxylamine hydrochloride (0.108 mmol) in water (30 mL). This mixture was then heated to gentle reflux until all the solids dissolved and was then heated for a further 15 min. The flask was removed from the heat and the solution was poured onto ice (500 g) with stirring. The resulting solid was collected by filtration, washed with water and air dried to give N-quinolin-6-yl-2-hydroxyiminoacatamide (94%). To a 1L, 3 necked flask was added concentrated sulfuric acid (100 mL). The acid was stirred and heated to 100 C. N-Quinolin-6-yl-2-hydroxyiminoacatamide (45 mmol) was added slowly and the resulting solution was heated for 1 h. The reaction mixture was carefully poured onto ice/water (750 mL) and stirred for about 1 h. The solids were collected by filtration, washed with water and air dried to give the desired compound, (46%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | To a solution of <strong>[580-15-4]quinolin-6-ylamine</strong> (5 g, 35 mmol) in cone. HCl (12 mL) was added dropwise an aqueous solution (4 mL) of NaNO2 (2.42 g, 35 mmol) at 0 C. The resulting mixture was stirred for Ih and then treated dropwise with a solution of SnCl2 2H2O (15.8 g, 70 mmol) in cone. HCl (15 mL) at 0 C. The reaction mixture was stirred for 2h at RT. The precipitate was collected and washed with EtOH and Et2O to yield 1-(quinolin-6-yl)hydrazine hydrochloride as a yellow powder (4.3 g, 77% yield), which was used for the next reaction without further purification. | |
77% | To a solution of <strong>[580-15-4]quinolin-6-ylamine</strong> (5 g, 35 mmol) in cone. HCl (12 mL) was added dropwise an aqueous solution (4 mL) of NaNO? (2.42 g, 35 mmol) at 0 DC. The resulting <n="84"/>mixture was stirred for Ih and then treated drop wise with a solution of S11CI2.2H2O (15.8 g, 70 mmol) in cone. HCl (15 niL) at 0 0C. The reaction mixture was stirred for 2h at RT. The precipitate was collected and washed with EtOH and Et2O to yield l-(quinolin-6-yl)hydrazine hydrochloride (4.3 g, 77% yield) as a yellow powder, which was used for the next reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | To a stirring solution of N- (3-trifluoromethyl-phenyl)-malonamic acid (1 g, 4.05 mmol) in anhydrous dichloromethane (100 mL) was added phosphorus pentachloride (842 mg, 4.05 mmol). The mixture was stirred at room temperature for 30 minutes. Then <strong>[580-15-4]6-aminoquinoline</strong> (874 mg, 6.0 mmol) was added and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with 50 ml dichloromethane and washed with 5% sodium bicarbonate. The organic layer was evaporated and the product was isolated as a white solid from a silica column (790 mg, 79%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | A mixture of 5-bromovaleryl chloride (4.03 g, 19.61 mmol) and dichloromethane (30 ml) was cooled to 0C. 6-Aminoquinoline (2.57 g, 17.8 mmol) <n="14"/>was added in small portions during 15 minutes. The temperature was allowed to reach room-temperature and stir for 15 h. Aqueous sodium hydroxide (40 ml, 1 M) was added and the mixture was extracted with dichloromethane (60 ml). The mixture was evaporated and diethylether (5 ml) was added, the solid was filtered and washed with 5 diethylether. Yield 4.95 g (90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Synthesis of 2, 5-dichloro-N-auinolin-6-vl-benzenesulfonamide, STX 934 (KRB01060):; To a solution of 2, 5-dichlorobenzenesulphonyl chloride (179 mg, 0.728 mmol) in dichloromethane (4 mL) was added pyridine (140 pL, 1.74 mmol) and the mixture was stirred under N2 for 5 min, after which time <strong>[580-15-4]6-aminoquinoline</strong> (100 mg, 0.694 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (168 mg, 69%), single spot at Rf 0.74 (ethyl acetate). mp 213.4-213. 8C, HPLC purity 99+% (tR 2.28 min in 10% water-acetonitrile).'H NMR (CDCI3) : No. 8.85 (1H, dd, J=4.2, 1.5 Hz), 8.09 (1H, d, J=8.4 Hz), 8.03-8. 00 (2H, m), 7.62 (1H, d, J=2.5 Hz), 7.56 (1H, s, N-H), 7.47-7. 38 (4H, m). LCMS: 351.10 (M-). FAB-MS (MH+, C15H10Cl2N2O2S) : calcd 352.9918, found 352.9922. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Synthesis of 4-propyl-N-quinolin-6-vl-benzenesulfonamide, STX 933 (KRB01059) :; To a solution of 4n-propylbenzenesulphonyl chloride (159 mg, 0.728 mmol) in dichloromethane (4 mL) was added pyridine (140 uL, 1.74 mmol) and the mixture was stirred under N2 for 5 min, after which time <strong>[580-15-4]6-aminoquinoline</strong> (100 mg, 0.694 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (210 mg, 93%), single spot at Rf 0.71 (ethyl acetate). mp 180.1-180. 7C, HPLC purity 99+% (tR 2.37 min in 10% water-acetonitrile).'H NMR (CDC13) : 5 8.83 (1H, dd, J=4.2, 1.7 Hz), 8.05 (1H, d, J=8.4 Hz), 7.97 (1H, d, J=9.2 Hz), 7.70 (2H, d, J=8.2 Hz), 7.57 (1H, d, J=2.5 Hz), 7.40-7. 34 (2H, m), 7.22 (2H, m), 6.85 (1H, s, N-H), 2.57 (2H, t, J=7.2 Hz), 1.57 (2H, sextet, J=7.2 Hz), 0.87 (3H, t, J=7.3 Hz). LCMS: 325.23 (M- ). FAB-MS (MH+, C18H18N2O2S) : calcd 327.1167, found 327.1167. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | b): Steps 13.1, 14.1-24.1 and 37.1-45.1: Compounds of Formula (III) (Method B) The intermediates shown in Table 2 are synthesized starting with compounds of Steps 13.2, 14.2, 19.2, 23.2, 41.2, 42.3, 44.2 and 45.2 described below, using the following procedure for the palladium catalyzed amination: A solution of the substituted [2-chloro-9-(tetrahydro-pyran-2-yl) -9H-purin-6-yl]-amine in dry/degassed toluene in added to sodium tert-butylate (1.4 eq. ) in a dry flask kept under argon. The appropriate heteroaryl/aryl-amine (1.1 eq. ) is added, the suspension is stirred for 20 min, heated to 110 C, and finally a solution of a catalytic amount of 2'-(dimethylamino)-2- biphenylyl-palladium(11) chloride dinorbornylphosphine complex (FLUKA, 0.02 eq. ) in dry/degassed toluene is added. The reaction mixtures is stirred at 110 C for 3 to 18 h, cooled to RT, and the required product is isolated by extraction from a 10 % sodium bicarbonate solution and ethyl acetate, followed by (i) flash silica chromatography or (ii) crystallization. For compounds of Steps 18.1,21.1, 22.1,23.1, and 37.1-40.1 the preparation of the aniline used as starting material is specifically described below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.8% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In diethylene glycol dimethyl ether; for 2.5h;Reflux; | 2. In a 250ml three-mouth flask, the purin of the above step (11.6g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0g), catalyst Pd(OAc)2 (0.3g), ligand 7 (0.3g), sodium tert-butoxide (5.4g) and ethylene glycol dimethyl ether (100ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filteration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the reisdue is purified by column chromatography on silica gel to obtain a conjugate (11.5g). The yield is about 76.8% on the basis of aminoquinoline. |
~ 76.8% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In 1,2-dimethoxyethane; for 2.5h;Reflux; | In a 250 ml three-mouth flask, the purin of the above step (11.6 g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0 g), catalyst Pd(OAc)2 (0.3 g), ligand 7 (0.3 g), sodium tert-butoxide (5.4 g) and ethylene glycol dimethyl ether (100 ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the residue is purified by column chromatography on silica gel to obtain a conjugate (11.5 g). The yield is about 76.8% on the basis of aminoquinoline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.6% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In diethylene glycol dimethyl ether; for 2.5h;Reflux; | 2. In a 250ml three-mouth flask, the solid purin (10.4g) of the above step, <strong>[580-15-4]6-aminoquinoline</strong> (5.0g), catalyst Pd(OAc)2 (0.3g), ligand 7 (0.3g), sodium tert-butoxide (5.4g) and ethylene glycol dimethyl ether (100ml) are added in turn. The above mixture is stirred and heated to reflux, and is reacted for about 2.5h under refluxing. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filteration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the reisdue is purified by column chromatography on silica gel to obtain white conjugate (11.5g). The yield is about 82.6% on the basis of aminoquinoline. |
~ 82.6% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In 1,2-dimethoxyethane; for 2.5h;Reflux; | In a 250 ml three-mouth flask, the solid purin (10.4 g) of the above step, <strong>[580-15-4]6-aminoquinoline</strong> (5.0 g), catalyst Pd(OAc)2 (0.3 g), ligand 7 (0.3 g), sodium tert-butoxide (5.4 g) and ethylene glycol dimethyl ether (100 ml) are added in turn. The above mixture is stirred and heated to reflux, and is reacted for about 2.5 h under refluxing. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the residue is purified by column chromatography on silica gel to obtain white conjugate (11.5 g). The yield is about 82.6% on the basis of aminoquinoline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.6% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In diethylene glycol dimethyl ether; for 2.5h;Reflux; | 2. In a 250ml three-mouth flask, the purin of the above step (11.0g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0g), catalyst Pd(OAc)2 (0.3g), ligand 7 (0.3g), sodium tert-butoxide (5.4g) and ethylene glycol dimethyl ether (100ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filteration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the reisdue is purified by column chromatography on silica gel to obtain a conjugate (11.9g). The yield is about 82.6% on the basis of aminoquinoline. |
~ 82.6% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In 1,2-dimethoxyethane;Reflux; | In a 250 ml three-mouth flask, the purin of the above step (11.0 g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0 g), catalyst Pd(OAc)2 (0.3 g), ligand 7 (0.3 g), sodium tert-butoxide (5.4 g) and ethylene glycol dimethyl ether (100 ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the residue is purified by column chromatography on silica gel to obtain a conjugate (11.9 g). The yield is about 82.6% on the basis of aminoquinoline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.2% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In diethylene glycol dimethyl ether; for 2.5h;Reflux; | 2. In a 250ml three-mouth flask, the purin of the above step (10.0g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0g), catalyst Pd(OAc)2 (0.3g), ligand 7 (0.3g), sodium tert-butoxide (5.4g) and ethylene glycol dimethyl ether (100ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filteration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the reisdue is purified by column chromatography on silica gel to obtain conjugate (10.7g). The yield is about 82.2% on the basis of aminoquinoline |
~ 82.2% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In 1,2-dimethoxyethane; for 2.5h;Heating; Reflux; | In a 250 ml three-mouth flask, the purin of the above step (10.0 g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0 g), catalyst Pd(OAc)2 (0.3 g), ligand 7 (0.3 g), sodium tert-butoxide (5.4 g) and ethylene glycol dimethyl ether (100 ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the residue is purified by column chromatography on silica gel to obtain conjugate (10.7 g). The yield is about 82.2% on the basis of aminoquinoline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In diethylene glycol dimethyl ether; for 2.5h;Reflux; | In a 250ml three-mouth flask, the purin of the above step (11.6g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0g), catalyst Pd(OAc)2 (0.3g), ligand 7 (0.3g), sodium tert-butoxide (5.4g) and ethylene glycol dimethyl ether (100ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5h. The completion of reaction is checked with TCL analysis. The reaction is cooled to room temperature. After filteration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the reisdue is purified by column chromatography on silica gel to obtain conjugate (11.5g). The yield is about 79.0% on the basis of aminoquinoline |
~ 79% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In 1,2-dimethoxyethane; for 2.5h;Heating; Reflux; | In a 250 ml three-mouth flask, the purin of the above step (11.6 g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0 g), catalyst Pd(OAc)2 (0.3 g), ligand 7 (0.3 g), sodium tert-butoxide (5.4 g) and ethylene glycol dimethyl ether (100 ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5 h. The completion of reaction is checked with TCL analysis. The reaction is cooled to room temperature. After filtration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the residue is purified by column chromatography on silica gel to obtain conjugate (11.5 g). The yield is about 79.0% on the basis of aminoquinoline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.8% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In diethylene glycol dimethyl ether; for 2.5h;Reflux; | 2. In a 250ml three-mouth flask, the purin of the above step (11.8g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0g), catalyst Pd(OAc)2 (0.3 g), ligand 7 (0.3g), sodium tert-butoxide (5.4g) and ethylene glycol dimethyl ether (100ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filteration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the reisdue is purified by column chromatography on silica gel to obtain a conjugate (12.0g). The yield is about 77.8% on the basis of aminoquinoline |
~ 77.8% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In 1,2-dimethoxyethane; for 2.5h;Reflux; | In a 250 ml three-mouth flask, the purin of the above step (11.8 g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0 g), catalyst Pd(OAc)2 (0.3 g), ligand 7 (0.3 g), sodium tert-butoxide (5.4 g) and ethylene glycol dimethyl ether (100 ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the residue is purified by column chromatography on silica gel to obtain a conjugate (12.0 g). The yield is about 77.8% on the basis of aminoquinoline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.7% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In diethylene glycol dimethyl ether; for 2.5h;Reflux; | 2. In a 250ml three-mouth flask, the purin of the above step (12.0g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0g), catalyst Pd(OAc)2 (0.3 g), ligand 7 (0.3g), sodium tert-butoxide (5.4g) and ethylene glycol dimethyl ether (100ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filteration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the reisdue is purified by column chromatography on silica gel to obtain white conjugate (12.2g). The yield is about 79.7% on the basis of aminoquinoline. |
~ 79.9% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In 1,2-dimethoxyethane; for 2.5h;Reflux; | In a 250 ml three-mouth flask, the purin of the above step (12.0 g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0 g), catalyst Pd(OAc)2 (0.3 g), ligand 7 (0.3 g), sodium tert-butoxide (5.4 g) and ethylene glycol dimethyl ether (100 ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the residue is purified by column chromatography on silica gel to obtain white conjugate (12.2 g). The yield is about 79.7% on the basis of aminoquinoline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.9% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In diethylene glycol dimethyl ether; for 2.5h;Reflux; | 2. In a 250ml three-mouth flask, the purin of the above step (11.5g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0g), catalyst Pd(OAc)2 (0.3g), ligand 7 (0.3g), sodium tert-butoxide (5.4g) and ethylene glycol dimethyl ether (100ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filteration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the reisdue is purified by column chromatography on silica gel to obtain a conjugate (11.3g). The yield is about 75.9% on the basis of aminoquinoline |
~ 75.9% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In 1,2-dimethoxyethane; for 2.5h;Reflux; | In a 250 ml three-mouth flask, the purin of the above step (11.5 g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0 g), catalyst Pd(OAc)2 (0.3 g), ligand 7 (0.3 g), sodium tert-butoxide (5.4 g) and ethylene glycol dimethyl ether (100 ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the residue is purified by column chromatography on silica gel to obtain a conjugate (11.3 g). The yield is about 75.9% on the basis of aminoquinoline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In diethylene glycol dimethyl ether; for 2.5h;Reflux; | 2. In a 250ml three-mouth flask, the purin of the above step (12.2g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0g), catalyst Pd(OAc)2 (0.3g), ligand 7 (0.3g), sodium tert-butoxide (5.4g) and ethylene glycol dimethyl ether (100ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filteration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the reisdue is purified by column chromatography on silica gel to obtain a conjugate (13.2g). The yield is about 83.0% on the basis of aminoquinoline |
~ 83% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In 1,2-dimethoxyethane; for 2.5h;Reflux; | In a 250 ml three-mouth flask, the purin of the above step (12.2 g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0 g), catalyst Pd(OAc)2 (0.3 g), ligand 7 (0.3 g), sodium tert-butoxide (5.4 g) and ethylene glycol dimethyl ether (100 ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the residue is purified by column chromatography on silica gel to obtain a conjugate (13.2 g). The yield is about 83.0% on the basis of aminoquinoline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
~ 83.6% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In 1,2-dimethoxyethane; for 2.5h;Reflux; | In a 250 ml three-mouth flask, the purin of the above step (11.0 g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0 g), catalyst Pd(OAc)2 (0.3 g), ligand 7 (0.3 g), sodium tert-butoxide (5.4 g) and ethylene glycol dimethyl ether (100 ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the residue is purified by column chromatography on silica gel to obtain white conjugate (11.7 g). The yield is about 83.6% on the basis of aminoquinoline. |
70% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In diethylene glycol dimethyl ether; for 2.5h;Reflux; | 2. In a 250ml three-mouth flask, the purin of the above step (11.0g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0g), catalyst Pd(OAc)2 (0.3g), ligand 7 (0.3g), sodium tert-butoxide (5.4g) and ethylene glycol dimethyl ether (100ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filteration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the reisdue is purified by column chromatography on silica gel to obtain white conjugate (11.7g). The yield is about 83.6% on the basis of aminoquinoline |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.2% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In diethylene glycol dimethyl ether; for 2.5h;Reflux; | 2. In a 250ml three-mouth flask, the purin of the above step (11.0g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0g), catalyst Pd(OAc)2 (0.3g), ligand 7 (0.3g), sodium tert-butoxide (5.4g) and ethylene glycol dimethyl ether (100ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filteration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the reisdue is purified by column chromatography on silica gel to obtain a conjugate (11.9g). The yield is about 82.2% on the basis of aminoquinoline. |
~ 82.2% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In 1,2-dimethoxyethane; for 2.5h;Reflux; | In a 250 ml three-mouth flask, the purin of the above step (11.0 g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0 g), catalyst Pd(OAc)2 (0.3 g), ligand 7 (0.3 g), sodium tert-butoxide (5.4 g) and ethylene glycol dimethyl ether (100 ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the residue is purified by column chromatography on silica gel to obtain a conjugate (11.9 g). The yield is about 82.2% on the basis of aminoquinoline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In diethylene glycol dimethyl ether; for 2.5h;Reflux; | 2. In a 250ml three-mouth flask, <strong>[580-15-4]6-aminoquinoline</strong> (5.0g), 2-chloro-N-methyl-N-ethyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine (10.3g), catalyst Pd(OAc)2 (0.3g), ligand 7 (0.3g), sodium tert-butoxide (5.4g) and ethylene glycol dimethyl ether (100ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filteration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the reisdue is purified by column chromatography on silica gel to obtain a conjugate (10.5g). The yield is about 75.0% on the basis of aminoquinoline |
~ 75% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In 1,2-dimethoxyethane; for 2.5h;Reflux; | In a 250 ml three-mouth flask, <strong>[580-15-4]6-aminoquinoline</strong> (5.0 g), 2-chloro-N-methyl-N-ethyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine (10.3 g), catalyst Pd(OAc)2 (0.3 g), ligand 7 (0.3 g), sodium tert-butoxide (5.4 g) and ethylene glycol dimethyl ether (100 ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the residue is purified by column chromatography on silica gel to obtain a conjugate (10.5 g). The yield is about 75.0% on the basis of aminoquinoline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.4% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In diethylene glycol dimethyl ether; for 2.5h;Reflux; | 2. In a 250ml three-mouth flask, the purin of the above step (8.9g), <strong>[580-15-4]6-aminoquinoline</strong> (4.5g), catalyst Pd(OAc)2 (0.3g), ligand 7 (0.3g), sodium tert-butoxide (5.4g) and ethylene glycol dimethyl ether (100ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for about 2.5h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filteration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the reisdue is purified by column chromatography on silica gel to obtain a conjugate (10.5g). The yield is about 86.4% on the basis of aminoquinoline. |
~ 86.4% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In 1,2-dimethoxyethane; for 2.5h;Reflux; | In a 250 ml three-mouth flask, the purin of the above step (8.9 g), <strong>[580-15-4]6-aminoquinoline</strong> (4.5 g), catalyst Pd(OAc)2 (0.3 g), ligand 7 (0.3 g), sodium tert-butoxide (5.4 g) and ethylene glycol dimethyl ether (100 ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for about 2.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the residue is purified by column chromatography on silica gel to obtain a conjugate (10.5 g). The yield is about 86.4% on the basis of aminoquinoline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.0% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In diethylene glycol dimethyl ether; for 2.5h;Reflux; | 2. In a 250ml three-mouth flask, the purin of the above step (12.0g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0g), catalyst Pd(OAc)2 (0.3g), ligand 7 (0.3g), sodium tert-butoxide (5.4g) and ethylene glycol dimethyl ether (100ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filteration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the reisdue is purified by column chromatography on silica gel to obtain a conjugate (12.7g). The yield is about 85.0% on the basis of aminoquinoline |
~ 85% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In 1,2-dimethoxyethane; for 2.5h;Reflux; | In a 250 ml three-mouth flask, the purin of the above step (12.0 g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0 g), catalyst Pd(OAc)2 (0.3 g), ligand 7 (0.3 g), sodium tert-butoxide (5.4 g) and ethylene glycol dimethyl ether (100 ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the residue is purified by column chromatography on silica gel to obtain a conjugate (12.7 g). The yield is about 85.0% on the basis of aminoquinoline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | 4-Bromo-/V-quinolin-6-yl-butyramide (Intermediate compound); A mixture of 5-bromobuturylchloride (5.00 g, 25.6 mmol) and dichloromethane (50 ml) was cooled to 0C. 6-Aminoquinoline (3.43 g, 23.3 mmol) was added in small portions during 15 minutes. The temperature was allowed to reach room-temperature and stir for 15 h. Aqueous sodium hydroxide (40 ml, 1 M) was added and the mixture was extracted with dichloromethane (60 ml). The mixture was evaporated and diethylether (5 ml) was added, the solid was filtered and washed with diethylether. Yield 5.9 g (86%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
~ 83.2% | With sodium t-butanolate; CyJohnPhos;palladium diacetate; In 1,2-dimethoxyethane; for 2.5h;Reflux; Heating; | In a 250 ml three-mouth flask, the purin of the above step (11.6 g), <strong>[580-15-4]6-aminoquinoline</strong> (5.0 g), catalyst Pd(OAc)2 (0.3 g), ligand 7 (0.3 g), sodium tert-butoxide (5.4 g) and ethylene glycol dimethyl ether (100 ml) are added in turn. The above mixture is stirred and heated to reflux, and under refluxing the above mixture is reacted for 2.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethylene glycol dimethyl ether for 2 times, and a filtrate is concentrated to dry and the residue is purified by column chromatography on silica gel to obtain a conjugate (12.1 g). The yield is about 83.2% on the basis of aminoquinoline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 120℃; for 19h; | Example 1 N2-(4-Diethylamino-1-methyl-butyl)-N4-uinolin-6-pyrimidine-2,4-diamine (CWB004) The mixture of <strong>[580-15-4]6-aminoquinoline</strong> (200 mg, 1.39 mmol), 2,4-dichloropyrimidine (249 mg, 1.67 mmol) and diisopropylethylamine (274 mg, 2.09 mmol) in isopropanol (4 mL) was stirred in a pressure bottle at 120 C for 19 h. The reaction mixture was evaporated under vacuum and the residue was purified by silica gel column using EtOAc/hepfiane 2/8, 1/1 and pure EtOAc as eluent to give 200 mg (56 %) of 6-(2-chloro-pyrimidin-4-ylamino)quinoline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In tetrahydrofuran; for 20h;Inert atmosphere; Reflux; | In a 200 mL four-necked flask, 5.00 g (34.7 mmol) of <strong>[580-15-4]6-aminoquinoline</strong> was dissolved in 100 mL of THF,Tert-butyl dicarbonate7.57 g (34.7 mmol), and the mixture was refluxed under a nitrogen atmosphere for 20 hours.After completion of the reaction, THF was removed by a rotary evaporator, ethyl acetate was added, washed with pure water and saturated brine, and dried with anhydrous magnesium sulfate. After removal of the anhydrous magnesium sulfate by filtration, the solvent was removed with a rotary evaporator, and the residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane (1: 4 by volume) to obtain a white solid. 29 g (86%) was obtained. |
84% | at 120℃; for 0.5h; | Synthesis of 90 A mixture of 89 (4.14 g, 28.71 mmol) and Boc2O (9.9 ml, 43.1 mmol) was stirred at 120C for 30 minutes. To the reaction solution, silica gel (30 ml) and toluene (100 ml) were added, followed by stirring at 80C for 1 hour. The reaction solution was allowed to return to room temperature and purified as it is by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate = 2/1, ethyl acetate) to obtain 90 (5.92 g, 84%) as a pale yellow solid. mp 132-133C APCI-MS m/z 245[M+H]+ |
81% | at 120℃; for 0.5h; | 1002211 A mixture of <strong>[580-15-4]6-aminoquinoline</strong> (1.73 g, 12 mmol) and Boc2O (3.91 g, 18 mmol) was stirred fro 30 mm at 120 C. To the reaction mixture, silica gel (12 mL) and toluene (40 mL) were added, followed by stirring for 1 hour at 80 C. The reaction mixture was cooled to RT, and purified by silica gel flash chromatography (hexane : EtOAc = 1: 1), giving the B 1 (2.4 g, 81 yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With nitric acid; In water; acetonitrile; at 80℃;Inert atmosphere; | General procedure: A mixture of α-ketoester 1 (1.5 mmol), arylamine 2 (1 mmol), HNO3 (10 mol %), and CH3CN (1.5 mL) was stirred at 80 C for the indicated time until complete consumption of the starting material as monitored by TLC analysis. The solvents were removed by rotary evaporation to provide raw products. Then the affording residue was purified by flash chromatography to give the desired products.1H NMR (600 MHz, CDCl3) δ[ppm] 1.58 (s, 3H, CH3), 3.74 (s, 3H, CH3), 3.82 (s, 3H, CH3), 4.98 (s, 1H, NH), 6.50 (s, 1H, CH), 7.19-7.20 (d, J = 8.8 Hz, 1H, ar), 7.24-7.25 (d, J = 4.3 Hz, 1H, CH, ar), δ= 7.72-7.73 (d, J = 8.4 Hz, 1H, CH, ar), 7.90-7.92 (d, J = 8.8 Hz, 1H, CH, ar), 8.65-8.66 (d, J = 4.0 Hz, 1H, CH, ar); 13C NMR (150 MHz, CDCl3) δ[ppm] 25.6, 52.3, 52.9, 58.0, 109.7, 120.4, 120.7, 125.5, 129.6, 130.6, 131.4, 132.2, 142.2, 144.0, 146.6, 168.8, 174.1; HRMS calcd for C17H17N2O4: 313.1183, found 313.1182. |
Tags: 6-Aminoquinoline | Quinolines | Amines | Other Fluorescence Labeling Reagents | Organic Building Blocks | Heterocyclic Building Blocks | Fluorescence Labeling Reagents | 580-15-4
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